Drug loaded microfiber sutures for ophthalmic application

ABSTRACT

Ophthalmic suture materials made from biocompatible and biodegradable polymers with high tensile strength for use in drug delivery, methods of making them, and method of using them for ocular surgery and repair have been developed. The suture materials are made from a combination of a biodegradable, biocompatible polymer and a hydrophilic biocompatible polymer. In a preferred embodiment the suture materials are made from a poly(hydroxyl acid) such as poly(1-lactic acid) and a polyalkylene oxide such as poly(ethylene glycol) or a polyalkylene oxide block copolymer. The sutures entrap (e.g., encapsulate) one or more therapeutic, prophylactic or diagnostic agents and provide prolonged release over a period of at least a week, preferably a month.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. ProvisionalApplication No. 61/642,535, filed May 4, 2012. The contents of thisapplication are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to surgical sutures for controlled drugdelivery, and in particular to ophthalmic sutures providing controlleddelivery.

BACKGROUND OF THE INVENTION

Invasive ophthalmic surgeries often lead to numerous complications forpatients, at least in part because patient compliance with prophylacticdrugs after ophthalmic surgery is relatively low and in part because theocular bioavailability is frequently low for common dosage forms. Thevast majority of ophthalmic drug formulations remain the traditionalsolutions, ointments and suspensions, by one estimate accounting forabout 90% of the global market of ophthalmic drug formulations.

Even when patient compliance is high, the ocular bioavailability ofdrugs applied topically as eye-drops is very poor. The absorption ofdrugs in the eye is severely limited by some protective mechanisms thatensure the proper functioning of the eye. The contact with the absorbingsurfaces (cornea and sclera) is reduced to a maximum of about twominutes. Dosage volumes are limited by drainage via the nasolacrimalsystem into the nasopharynx and the gastrointestinal tract. Lacrimationand the physiological tear turnover (16% per minute in humans in normalconditions) are often increased by the instillation even of mildlyirritating solutions, leading to more rapid clearance of the applieddosage form.

Trabeculectomy is an ophthalmic surgical procedure used in the treatmentof glaucoma. Removing part of the eye's trabecular meshwork and adjacentstructures allows drainage of aqueous humor from within the eye tounderneath the conjunctiva to relieve intraocular pressure. The scleralflap is typically sutured loosely back in place with several sutures.Common complications include blebitis (an isolated bleb infectiontypically caused by microorganisms such as Staphylococcus epidermidis,Propriobacterium acnes, or Staphylococcus aureus), inflammation, andbleb-associated endophthalmitis.

Endophthalmitis is an inflammation of the ocular cavities and theiradjacent structures. It is a possible complication of all intraocularsurgeries, particularly cataract surgery, which can result in loss ofvision or the eye itself. Endophthalmitis is usually accompanied bysevere pain, loss of vision, and redness of the conjunctiva and theunderlying episclera. Infectious etiology is the most common and variousbacteria and fungi have been isolated as the cause of theendophthalmitis. The patient needs urgent examination by anophthalmologist and/or vitreo-retina specialist who will usually decidefor urgent intervention to provide intravitreal injection of potentantibiotics and also prepare for an urgent pars plana vitrectomy asneeded. Enucleation may be required to remove a blind and painful eye.

Opthalmic sutures are commonly used during ophthalmic surgicalprocedures, including trabeculectomy as well as pterygium removal,cataract surgery, strabismus correction surgery, penetratingkeratoplasty, sclerectomy, and conjunctival closure. The choice ofsuture material can strongly impact the occurrence of complicationsrelated to infection and inflammation post ophthalmic surgery, eithercausing irritation and local inflammation or providing a substrate formicroorganism growth. The suture materials typically employed includenonbiodegradable ophthalmic suture materials such as ETHILON® nylonsuture, MERSILENE® polyester fiber suture, PERMA-HAND® silk suture,PROLENE® polypropylene suture, each commercially available from Ethicon,Somerville, N.J.; and VASCUFIL® coated monofilament suture composed of acopolymer of butylene terephthalate and polyteramethylene ether glycol,MONOSOF˜DERMALON® monofilament nylon sutures composed of long-chainaliphatic polymers Nylon 6 and Nylon 6.6, NOVAFIL® monofilament suturescomposed of a copolymer of butylene terephthalate and polyteramethyleneether glycol, SOF SILK® braided sutures composed of fibroin,TI-CRON-SURGIDAC® braided polyester sutures composed of polyesterterephthalate, SURGILON® braided nylon sutures composed of thelong-chain aliphatic polymers Nylon 6 and Nylon 6.6 and SURGIPROII-SURGIPRO® sutures composed of polypropylene, each commerciallyavailable from U.S. Surgical, Norwalk, Conn.

Ideally, ophthalmic suture materials would be biodegradable andbiodegradable over the useful suture lifetime, retaining the requisitetensile strength and capable of delivering therapeutic or prophylacticagents to increase patient success. For pterygium removal, cataractsurgery and strabismus correction surgery, sutures could be used toclose the wound and release antibiotic and anti-inflammatory drugs. Fortrabeculectomy surgeries, sutures could be placed on sclera flapsproviding local chemotherapeutic agents, decreasing production of scartissue, and also, on conjunctival closure with antibiotic release. Inpenetrating keratoplasty, the sutures hold the graft, as well as releaseantibiotic and immunosuppressant agents.

Therefore, it is an object of the invention to provide ophthalmicsutures that are biocompatible and biodegradable and retain therequisite tensile strength over the useful life of the suture.

It is further an object of the invention to provide ophthalmic suturescapable of delivering an effective amount of one or more therapeutic orprophylactic agents to the ocular region over an extended period oftime.

It is further an object of the invention to provide ophthalmic sutureshaving a diameter allowing for use in ophthalmic procedures whilecausing little to no irritation of the surrounding tissue.

It is further an object of the invention to provide the ophthalmicsutures having a higher tensile strength than commonly employedophthalmic suture materials of a similar diameter.

It is further an object of the invention to provide methods of makingophthalmic sutures that are biocompatible and biodegradable and capableof delivering one or more therapeutic agents.

It is further an object of the invention to provide method of ophthalmicsurgery and repair using the sutures described herein to increasepatient comfort and/or success as compared to traditional ophthalmicsuture materials.

SUMMARY OF THE INVENTION

Ophthalmic suture materials made from biocompatible and biodegradablepolymers with high tensile strength for use in drug delivery, methods ofmaking them, and method of using them for ocular surgery and repair havebeen developed. The suture materials are made from a combination of abiodegradable, biocompatible polymer and a hydrophilic biocompatiblepolymer. In a preferred embodiment the suture materials are made from apoly(hydroxyl acid) such as poly(l-lactic acid) and a polyalkylene oxidesuch as poly(ethylene glycol) or a polyalkylene oxide block copolymer.The sutures entrap (e.g., encapsulate) one or more therapeutic,prophylactic or diagnostic agents and provide prolonged release over aperiod of at least a week, preferably a month.

Exemplary agents include, but are not limited to, anti-inflammatoryagents such as dexamethasone, prednisolone, triamcinolone, andflurbiprofen, released in an effective amount to prevent post-operativeinflammation resulting from the ophthalmic procedure or from thepresence of the suture. Other therapeutic agents include neomycin,polymyxin B, bacitracin, gramicidin, gentamicin, oyxtetracycline,ciprofloxacin, ofloxacin, miconazole, itraconazole, trifluridine, andvidarabine to prevent or inhibit the occurrence of post-operative ocularinfections. Sutures release anti-infective agents for a period of atleast seven days, more preferably 30 days, in an effective amount toprevent infection.

The sutures can be monofilament, multi-filament or braided sutures. Foruse in ophthalmic procedures, the sutures will typically have a diameterof between approximately 10 μm and 100 μm, preferably between 10 μm and90 μm, more preferably between about 10 μm to about 70 μm, mostpreferably between about 20 μm and 60 μm. In particular embodiments, thediameter is between about 40 μm and 50 μm. The fiber diameters in theexamples correspond to 7.0 to 10.0 (USP designation), diameters commonlyused in ophthalmic surgeries. To prevent suture breakage whilemaintaining flexibility and patient comfort, the sutures maintain hightensile strengths even at smaller overall diameters. In a preferredembodiment, a biodegradable suture material is provided having adiameter of less than 80 μm and a tensile strength of greater than 700MPa, preferably greater than 1.0 GPa.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the in vitro drug release in PBS buffer (%release) as a function of time (days) for 1 cm of levofloxacin-PLLA-PEG2% fibers prepared in Example 1.

FIG. 2 is a graph showing the in vitro drug release of 4 mg oflevofloxacin loaded PLLA-PEG and PLLA-F127 fibers in tubes filled withPBS and kept in an incubator shaker.

FIG. 3 is a graph showing the amount of levofloxacin released (ng) intothe aqueous humor, the cornea, and in total from approximately 1 cmophthalmic sutures made from PLLA-PEG fibers placed on the cornealstroma of female Sprague-Dawley rats as a function of time (hours)

FIG. 4 is a graph showing the inhibition zone of bacterial growth (cm²)as a function of the time (days) for levofloxacin-PLLA-PEG fibersincubated in PBS buffer and measured via retrieval and incubation at 37°C. overnight (24 hours) on LB agar plates inoculated with Staphylococcusepidermidis Negative and positive controls were done as well.

DETAILED DESCRIPTION OF THE INVENTION

Biodegradable ophthalmic sutures and suture materials are provided madefrom a biodegradable, biocompatible polymer. An exemplary biodegradable,biocompatible polymer is poly(l-lactic acid) (PLLA). The sutures in someembodiments contain one or more hydrophilic polymers, preferablypoly(ethylene glycol) (PEG). The sutures contain one or moretherapeutic, prophylactic, or diagnostic agents. In preferredembodiments, the suture contains anti-infective agents and/oranti-inflammatory agents.

I. Definitions

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, andcycloalkyl-substituted alkyl groups.

In preferred embodiments, a straight chain or branched chain alkyl has30 or fewer carbon atoms in its backbone (e.g., C₁-C₃₀ for straightchains, C₃-C₃₀ for branched chains), preferably 20 or fewer, morepreferably 15 or fewer, most preferably 10 or fewer. Likewise, preferredcycloalkyls have from 3-10 carbon atoms in their ring structure, andmore preferably have 5, 6 or 7 carbons in the ring structure. The term“alkyl” (or “lower alkyl”) as used throughout the specification,examples, and claims is intended to include both “unsubstituted alkyls”and “substituted alkyls”, the latter of which refers to alkyl moietieshaving one or more substituents replacing a hydrogen on one or morecarbons of the hydrocarbon backbone. Such substituents include, but arenot limited to, halogen, hydroxyl, carbonyl (such as a carboxyl,alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester,a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate,phosphonate, a hosphinate, amino, amido, amidine, imine, cyano, nitro,azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl,sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic orheteroaromatic moiety.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto ten carbons, more preferably from one to six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths. Throughout the application, preferred alkylgroups are lower alkyls. In preferred embodiments, a substituentdesignated herein as alkyl is a lower alkyl.

It will be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate. For instance, the substituents of a substituted alkyl mayinclude halogen, hydroxy, nitro, thiols, amino, azido, imino, amido,phosphoryl (including phosphonate and phosphinate), sulfonyl (includingsulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, aswell as ethers, alkylthios, carbonyls (including ketones, aldehydes,carboxylates, and esters), —CF₃, —CN and the like. Cycloalkyls can besubstituted in the same manner.

The terms “biocompatible” and “biologically compatible”, as usedinterchangeably herein, refer to materials that are, with anymetabolites or degradation products thereof, generally non-toxic to therecipient, and cause no significant adverse effects to the recipient.Generally speaking, biocompatible materials are materials which do notelicit a significant inflammatory or immune response when administeredto a patient. In some embodiments a biocompatible material elicits nodetectable change in one or more biomarkers indicative of an immuneresponse. In some embodiments, a biocompatible material elicits nogreater than a 10% change, no greater than a 20% change, or no greaterthan a 40% change in one or more biomarkers indicative of an immuneresponse.

The term “biodegradable”, as used herein, means that the material, fiberor suture degrades or breaks down into its component subunits, ordigestion products, e.g., by a biochemical process, of the material intosmaller (e.g., non-polymeric) subunits. In some embodiments, abiodegradable material, fiber or suture degrades into CO₂, H₂O, andother biomass materials. In some embodiments, the degradation occursover a period less than 30 days, less than 60 days, less than 90 days,less than 120 days, less than 180 days, less than 1 year. In someembodiments the degradation occurs over a period greater than 30 days,greater than 60 days, greater than 90 days, greater than 120 days,greater than 180 days, or greater than 1 year. In certain embodimentsdegradation of a material, fiber or suture is said to be complete whenat least 80% by mass has degraded, when at least 85% by mass hasdegraded, when at least 90% by mass has degraded, when at least 95% bymass has degraded, or when at least 99% by mass has degraded. Thebiodegradation rate depends upon several factors, both environmental andmaterial. Non-limiting examples of environmental factors influencingbiodegradation rates include temperature, pH, oxygen concentrations, andmicrobial and enzymatic activities. Non-limiting examples of materialproperties influencing biodegradation rates include degree of branchingof the polymer chains, the presence and amount of hydrophilic groups,stereochemistry, molecular weight, the degree of crystallinity, thecrosslinking, surface roughness, and the surface to volume ratio.

The term “inhibit,” “inhibiting,” or “inhibition” refers to a decreasein activity, response, condition, disease, or other biologicalparameter. This can include but is not limited to the complete ablationof the activity, response, condition, or disease. This may also include,for example, a 10% reduction in the activity, response, condition, ordisease as compared to the native or control level. Thus, the reductioncan be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount ofreduction in between as compared to native or control levels.

The term “subject” refers to any individual who is the target ofadministration. The subject can be a vertebrate, for example, a mammal.Thus, the subject can be a human. The term does not denote a particularage or sex. The term “patient” refers to a subject afflicted with adisease or disorder. The term “patient” includes human and veterinarysubjects. The term “patient” or “subject” to be treated refers to eithera human or non-human animal.

The term “prodrug”, as used herein, refers to compounds which, underphysiological conditions, are converted into the therapeutically activeagents of the present invention. A common method for making a prodrug isto include selected moieties which are hydrolyzed under physiologicalconditions to reveal the desired molecule. In other embodiments, theprodrug is converted by an enzymatic activity of the host animal.

The term “prevent,” “preventing,” or “prevention” does not requireabsolute forestalling of the condition or disease but can also include areduction in the onset or severity of the disease or condition orinhibition of one or more symptoms of the disease or disorder.

The term “pharmaceutically acceptable salt”, as used herein, refer toderivatives of the compounds defined herein, wherein the parent compoundis modified by making acid or base salts thereof. Example ofpharmaceutically acceptable salts include but are not limited to mineralor organic acid salts of basic residues such as amines; and alkali ororganic salts of acidic residues such as carboxylic acids. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. Suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric acids; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic,oxalic, and isethionic salts.

The pharmaceutically acceptable salts of the compounds can besynthesized from the parent compound, which contains a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000, p. 704; and “Handbook of Pharmaceutical Salts:Properties, Selection, and Use,” P. Heinrich Stahl and Camille G.Wermuth, Eds., Wiley-VCH, Weinheim, 2002.

As generally used herein “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problems or complicationscommensurate with a reasonable benefit/risk ratio.

The term “treat” or “treatment” refers to the medical management of asubject with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder.

II. Ophthalmic Sutures

A. Suture Properties

1. Suture Diameter

Suture diameters are defined by the United States Pharmacopeia (U.S.P.).Modern sutures range from #5 (heavy braided suture for orthopedics) to#11-0 (fine monofilament suture for ophthalmics). Suitable diameters forophthalmic use are USP size 6.0-11.0, preferably 7.0-11.0, morepreferably 8.0-11.0, most preferably 9.0-11.0.

TABLE 1 Diameter for various USP size sutures as well as the Knot-pulltensile strength in Newtons and grams. Knot-pull Knot-pull Limits onAverage φ (μm) tensile tensile USP Size Min Max strength (N) strength(g) 10-0 20 29 0.24* 24.47 Straight pull 9-0 30 39 0.49* 49.96 8-0 40 490.69 70.36 7-0 50 69 1.37 139.70 6-0 70 99 2.45 249.83

Table 2 provides the Typical USP tensile strength values for varioussized commercially available sutures.

TABLE 2 Size Diameter (mm) Tensile Strength (Mpa) 9.00 0.030 693.56 8.000.040 549.36 7.00 0.050 698.09 6.00 0.070 636.94

The sutures can be multi-filament or braided sutures, or can bemonofilament. For use in ophthalmic procedures, the sutures willtypically have a diameter of approximately 10 μm (USP 11.0) toapproximately 100 μm (USP 6.0), preferably 10 μm (USP 11.0) to about 70μm (USP 7.0), more preferably from about 10 μm (USP 11.0) to about 50 μm(USP 8.0), most preferably from about 10 μm (USP 11.0) to about 40 μm(USP 9.0). In particular embodiments, the diameter is from about 20 μmto about 50 μm (USP 8.0, 9.0, or 10.0). USP 11.0 and 10.0 are often usedin the most delicate surgeries, such as in the eye.

In other embodiments, the sutures have the above diameter and a tensilestrength of at least about 600, 650, 700, 750, 800, 850, 900, 950, or1000 MPa. In particular embodiments, the sutures have a tensile strengthfrom about 1000 to about 2500 MPa, preferably from about 1200 to about2500 MPa, more preferably from about 1300 to about 2300 MPa. The suturesshould retain the tensile strength for the requisite period of time.

A. Biodegradable Polymers

The sutures contain one or more biodegradable, biocompatible polymers.The one or more biodegradable, biocompatible polymers can behomopolymers or copolymers.

Examples of suitable biodegradable, biocompatible polymers. includepolyhydroxyacids such as poly(lactic acid), poly(glycolic acid), andpoly(lactic acid-co-glycolic acids); polyhydroxyalkanoates such aspoly-3-hydroxybutyrate or poly-4-hydroxybutyrate; polycaprolactones;poly(orthoesters); polyanhydrides; poly(phosphazenes);poly(hydroxyalkanoates); poly(lactide-co-caprolactones); polycarbonatessuch as tyrosine polycarbonates; polyamides (including synthetic andnatural polyamides), polypeptides, and poly(amino acids);polyesteramides; polyesters; poly(dioxanones); poly(alkylene alkylates);hydrophobic polyethers; polyurethanes; polyetheresters; polyacetals;polycyanoacrylates; polyacrylates; polymethylmethacrylates;polysiloxanes; poly(oxyethylene)/poly(oxypropylene) copolymers;polyketals; polyphosphates; polyhydroxyvalerates; polyalkylene oxalates;polyalkylene succinates; poly(maleic acids), as well as copolymersthereof.

In one embodiment, the biodegradable, biocompatible polymer is selectedfrom the group consisting of polylactides, polyglycolides,poly(lactide-co-glycolide)s, polylactic acids, polyglycolic acids,poly(lactic acid-co-glycolic acid)s, polycaprolactones, polycarbonates,polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters,polyacetyls, polycyanoacrylates, polyetheresters, polydioxanones,polyalkylene alkylates, copolymers of polyethylene glycol andpolylactides or poly(lactide-co-glycolide)s, biodegradablepolyurethanes, and certain types of protein and polysaccharide polymers,as well as blends and copolymers thereof. In a further embodiment, thebiodegradable polymer is selected from the group consisting ofpolyhydroxy acids, polylactic acids, polylactides, polyglycolides,polyglycolic acids, and copolymers thereof as well as derivativesthereof. The biodegradable polymers may also include or consist ofpolyanhydrides, polyorthoesters, and polysaccharide polymers.

In one embodiment, the biodegradable polymer ispoly-(D,L-lactide-co-glycolide). In some embodiments, thepoly-(D,L-lactide-co-glycolide) contains about 55 to about 80 mole %lactide monomer and about 45 to about 20 mole % glycolide. Thepoly-(D,L-lactide-co-glycolide) may also contain about 65 to about 75mole % lactide monomer and about 35 to about 25 mole % glycolide. Thepoly-(D,L-lactide-co-glycolide) can contain terminal acid groups.

The biodegradable, biocompatible polymer can be a polylactic acidpolymer or copolymer containing lactide units substituted with alkylmoieties. Examples include, but are not limited to,poly(hexyl-substituted lactide) or poly(dihexyl-substituted lactide).

The molecular weight of the one or more biodegradable, biocompatiblepolymer can be varied to prepare sutures and fibers having the desiredproperties, such as drug release rate, for specific applications. Theone or more biodegradable, biocompatible polymers can have a molecularweight of about 150 Da to 1 MDa. In certain embodiments, thebiodegradable, biocompatible polymers has a molecular weight of betweenabout 1 kDa and about 200 kDa, more preferably between about 50 kDa andabout 150 kDa.

The amount of polymer or polymers in the finished fibers can vary. Insome embodiments, the concentration of the polymer or polymers in thefinished fibers/sutures is from about 75 wt % to about 85% by weight ofthe finished fibers, preferably from about 77% to about 83% by weight ofthe finished fibers.

B. Hydrophilic Polymers

In some embodiments the suture contains one or more hydrophilicpolymers. The hydrophilic polymer can be, for example, a poly(alkyleneglycol), a polysaccharide, poly(vinyl alcohol), polypyrrolidone, apolyoxyethylene block copolymer (PLURONIC®) or a copolymers thereof. Inpreferred embodiments, the one or more hydrophilic polymers are, or arecomposed of, polyethylene glycol (PEG).

Each hydrophilic polymer can independently contain any hydrophilic,biocompatible (i.e., it does not induce a significant inflammatory orimmune response), non-toxic polymer or copolymer. Examples of suitablepolymers include, but are not limited to, poly(alkylene glycols) such aspolyethylene glycol (PEG), poly(propylene glycol) (PPG), and copolymersof ethylene glycol and propylene glycol, poly(oxyethylated polyol),poly(olefinic alcohol), polyvinylpyrrolidone),poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate),poly(saccharides), poly(amino acids), poly(hydroxy acids), poly(vinylalcohol), and copolymers, terpolymers, and mixtures thereof.

In preferred embodiments, the one or more hydrophilic polymers are orcontain a poly(alkylene glycol) chain. The poly(alkylene glycol) chainsmay contain between 1 and 500 repeat units, more preferably between 40and 500 repeat units. Suitable poly(alkylene glycols) includepolyethylene glycol, polypropylene 1,2-glycol, poly(propylene oxide),polypropylene 1,3-glycol, and copolymers thereof.

In some embodiments, the one or more hydrophilic polymers are copolymerscontaining one or more blocks of polyethylene oxide (PEO) along with oneor more blocks composed of other biocompatible polymers (for example,poly(lactide), poly(glycolide), poly(lactide-co-glycolide), orpolycaprolactone). The one or more hydrophilic polymer segments can becopolymers containing one or more blocks of PEO along with one or moreblocks containing polypropylene oxide (PPO). Specific examples includetriblock copolymers of PEO-PPO-PEO, such as POLOXAMERS™ and PLURONICS™.

In preferred embodiments, the one or more hydrophilic polymers are PEGchains. In such cases, the PEG chains can be linear or branched, such asthose described in U.S. Pat. No. 5,932,462. In certain embodiments, thePEG chains are linear.

The amount of the hydrophilic polymer or polymers in the finished fiberscan vary. In some embodiments, the amount of hydrophilic polymer orpolymers in the finished fibers is from about 1% to about 10% by weightof the finished fibers, preferably from about 2% to about 5% by weightof the finished fibers, more preferably from about 3% to about 5% byweight of the finished fibers.

The inclusion of the hydrophilic polymer component in the ophthalmicsutures results in a significantly higher burst release and release ofthe agent over a longer period of time e.g., more than three months.

D. Active Agents

The sutures contain a therapeutic, diagnostic, and/or prophylacticagent. The active agent can be a small molecule active agent and/or abiomolecule, such as an enzyme, protein, growth factor, polypeptide,polysaccharide, lipid, or nucleic acid. Suitable small molecule activeagents include organic and organometallic compounds. In some instances,the small molecule active agent has a molecular weight of less thanabout 2000 g/mol, preferably less than about 1500 g/mol, more preferablyless than about 1200 g/mol, most preferably less than about 1000 g/mol.In other embodiments, the small molecule active agent has a molecularweight less than about 500 g/mol. The small molecule active agent can bea hydrophilic, hydrophobic, or amphiphilic compound. Biomoleculestypically have a molecular weight of greater than about 2000 g/mol andmay be composed of repeat units such as amino acids (peptide, proteins,enzymes, etc.) or nitrogenous base units (nucleic acids). In preferredembodiments, the active agent is an ophthalmic therapeutic, prophylacticor diagnostic agent. Non-limiting examples of ophthalmic agents includeanti-glaucoma agents, anti-angiogenesis agents, anti-infective agents,anti-inflammatory agents, growth factors, immunosuppressant agents,anti-allergic agents, and combinations thereof.

Representative anti-glaucoma agents include prostaglandin analogs suchas travoprost, bimatoprost, and latanoprost, beta-andrenergic receptorantagonists such as timolol, betaxolol, levobetaxolol, and carteolol,alpha-2 adrenergic receptor agonists such as brimonidine andapraclonidine), carbonic anhydrase inhibitors (such as brinzolamide,acetazolamine, and dorzolamide, miotics (i.e., parasympathomimetics,such as pilocarpine and ecothiopate), seretonergics muscarinics,dopaminergic agonists, and adrenergic agonists such as apraclonidine andbrimonidine.

Representative anti-angiogenesis agents include, but are not limited to,antibodies to vascular endothelial growth factor (VEGF) such asbevacizumab (AVASTIN®) and rhuFAb V2 (ranibizumab, LUCENTIS®), and otheranti-VEGF compounds; MACUGEN® (pegaptanim sodium, anti-VEGF aptamer orEYE001) (Eyetech Pharmaceuticals); pigment epithelium derived factor(s)(PEDF); COX-2 inhibitors such as celecoxib (CELEBREX®) and rofecoxib(VIOXX®); interferon alpha; interleukin-12 (IL-12); thalidomide(THALOMID®) and derivatives thereof such as lenalidomide (REVLIMID®);squalamine; endostatin; angiostatin; ribozyme inhibitors such asANGIOZYME® (Sirna Therapeutics); multifunctional antiangiogenic agentssuch as NEOVASTAT® (AE-941) (Aeterna Laboratories, Quebec City, Canada);receptor tyrosine kinase (RTK) inhibitors such as sunitinib (SUTENT®);tyrosine kinase inhibitors such as sorafenib (Nexavar®) and erlotinib(Tarceva®); antibodies to the epidermal grown factor receptor such aspanitumumab (VECTIBIX®) and cetuximab (ERBITUX®), as well as otheranti-angiogenesis agents known in the art.

Anti-infective agents include antiviral agents, antibacterial agents,antiparasitic agents, and anti-fungal agents. Representative antiviralagents include ganciclovir and acyclovir. Representative antibioticagents include aminoglycosides such as streptomycin, amikacin,gentamicin, and tobramycin, ansamycins such as geldanamycin andherbimycin, carbacephems, carbapenems, cephalosporins, glycopeptidessuch as vancomycin, teicoplanin, and telavancin, lincosamides,lipopeptides such as daptomycin, macrolides such as azithromycin,clarithromycin, dirithromycin, and erythromycin, monobactams,nitrofurans, penicillins, polypeptides such as bacitracin, colistin andpolymyxin B, quinolones, sulfonamides, and tetracyclines. In a preferredembodiment the anti-infective agent is a fluoroquinolone, such aslevofloxacin.

In some cases, the active agent is an anti-allergic agent such asolopatadine and epinastine.

Anti-inflammatory agents include both non-steroidal and steroidalanti-inflammatory agents. Suitable steroidal active agents includeglucocorticoids, progestins, mineralocorticoids, and corticosteroids.

In particular embodiments, the therapeutic and/or prophylactic agent isselected from antibiotics, corticosteroids, anti-inflammatory agents,chemotherapeutic agents, immunosuppressant agents, and combinationsthereof. Specific combinations include, but are not limited to,antibiotics and corticosteroids, antibiotics and anti-inflammatoryagents, antibiotics and chemotherapeutic agents, and antibiotics andimmunosuppressant agents.

The ophthalmic drug may be present in its neutral form, or in the formof a pharmaceutically acceptable salt. In some cases, it may bedesirable to prepare a formulation containing a salt of an active agentdue to one or more of the salt's advantageous physical properties, suchas enhanced stability or a desirable solubility or dissolution profile.

Generally, pharmaceutically acceptable salts can be prepared by reactionof the free acid or base forms of an active agent with a stoichiometricamount of the appropriate base or acid in water or in an organicsolvent, or in a mixture of the two; generally, non-aqueous media likeether, ethyl acetate, ethanol, isopropanol, or acetonitrile arepreferred. Pharmaceutically acceptable salts include salts of an activeagent derived from inorganic acids, organic acids, alkali metal salts,and alkaline earth metal salts as well as salts formed by reaction ofthe drug with a suitable organic ligand (e.g., quaternary ammoniumsalts). Lists of suitable salts are found, for example, in Remington'sPharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000, p. 704. Examples of ophthalmic drugs sometimesadministered in the form of a pharmaceutically acceptable salt includetimolol maleate, brimonidine tartrate, and sodium diclofenac.

In some cases, the active agent is a diagnostic agent imaging orotherwise assessing the eye. Exemplary diagnostic agents includeparamagnetic molecules, fluorescent compounds, magnetic molecules, andradionuclides, x-ray imaging agents, and contrast media.

The agent or agents can be directly dispersed or incorporated into thefibers as particles using common solvent with the polymer, for examplesmicroparticles and/or nanoparticles of drug alone, or microparticlesand/or nanoparticles containing a matrix, such as a polymer matrix, inwhich the agent or agents are encapsulated or otherwise associated withthe particles.

The concentration of the drug in the finished fiber can vary. In someembodiments, the amount of drug is between about 0.1% and about 50% byweight, preferably between about 1% and about 40% by weight, morepreferably between about 3% and about 40% by weight, most preferablybetween about 5% and about 40% by weight of the finished fibers.

In particular embodiments, the agent is an antimicrobial agent and theconcentration of the agent is between about 30% to about 40% by weightof the finished fibers. The fiber releases an effective amount of theantimicrobial agent to inhibit/prevent bacterial growth for at least 2weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 16 weeks, or 20weeks.

III. Methods of Making Sutures

The sutures can be prepared using techniques known in the art. In someembodiments, a polymer-drug solution is prepared by dissolving thepolymers used to form the fiber matrix (e.g., biodegradable and/orbiocompatible polymer), the agent to be delivered, and optionally ahydrophilic polymer or polymers. These materials are typically dissolvedin an organic solvent, such as chloroform. The solutions can bemaintained at room temperature and stirred until a homogeneous solutionis obtained. In some embodiments, the solution is stirred at least oneday, such as two days or three days.

The fibers can be prepared using a polymer extrusion system. In oneembodiment, fiber extrusion platform includes a high voltage powersupply, syringe pump, needle syringe and a grounded 20 cm diametermotor-run rotating metal disc. High voltage DC power was applied to thesolution by clamping electrode on the blunted needle. With 5 kV appliedvoltage and the 12 ml/h feed rate, applied voltage initiates a polymerjet, which lands in 100% ethanol (Pharmco-Aaper, Brookfield, Conn.) bathon the metal disk to extract the solvent. The liquid reservoir was 5 cmaway from the needle opening. Angular velocity of the collection wheelwas adjusted by a DC motor controller (Dart 15DVE) unit, usually in therange of 20˜40 rotation/min or 20-40 cm/sec. The fibers were collectedfrom the disc and dried in a vacuum chamber for two days, allowing thesolvents to evaporate. The fibers were then stored in dry conditions andkept in −20° C. for further analyses. The same procedure was repeatedwith the control solution.

III. Methods of Using

The fibers can be used simultaneously as drug delivery vehicles andsutures to close wounds in the eye, such as those created inophthalmologic surgery or due to injury or trauma to the eye. Thesutures can be modified by inclusion of a hydrophilic polymer such asPEG or a POLOXAMER® to provide a burst release of an active agent, suchas an antimicrobial agent, followed by sustained release over anextended period of time, such as one week, two weeks, 4 weeks, 6 weeks,8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, or 20 weeks.

The sutures typically have a diameter from about 20 to about microns,preferably from 30 to about 50 microns, more preferably from about 40 toabout 50 microns. The sutures typically have a tensile strength of atleast about 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600,1700, or 1800 MPa.

The sutures can be used in a variety of ophthalmic procedures known inthe art. Examples include, but are not limited to, trabeculectomy aswell as pterygium removal, cataract surgery, strabismus correctionsurgery, penetrating keratoplasty, sclerectomy, and conjunctivalclosure.

Trabeculectomy is an ophthalmic surgical procedure used in the treatmentof glaucoma. Removing part of the eye's trabecular meshwork and adjacentstructures allows drainage of aqueous humor from within the eye tounderneath the conjunctiva to relieve intraocular pressure. The scleralflap is typically sutured loosely back in place with several sutures.Common complications include blebitis (an isolated bleb infectiontypically caused by microorganisms such as Staphylococcus epidermidis,Propriobacterium acnes, or Staphylococcus aureus), inflammation, andbleb-associated endophthalmitis.

Endophthalmitis is an inflammation of the ocular cavities and theiradjacent structures. It is a possible complication of all intraocularsurgeries, particularly cataract surgery, which can result in loss ofvision or the eye itself. Endophthalmitis is usually accompanied bysevere pain, loss of vision, and redness of the conjunctiva and theunderlying episclera. Infectious etiology is the most common and variousbacteria and fungi have been isolated as the cause of theendophthalmitis. The patient needs urgent examination by anophthalmologist and/or vitreo-retina specialist who will usually decidefor urgent intervention to provide intravitreal injection of potentantibiotics and also prepare for an urgent pars plana vitrectomy asneeded. Enucleation may be required to remove a blind and painful eye.

Ideally, ophthalmic suture materials would be biodegradable andbiodegradable over the useful suture lifetime, retaining the requisitetensile strength and capable of delivering therapeutic or prophylacticagents to increase patient success, however, it is not essential thesuture be biodegradable. For pterygium removal, cataract surgery andstrabismus correction surgery, sutures can be used to close the woundand release antibiotic and anti-inflammatory drugs. For trabeculectomysurgeries, sutures can be placed on sclera flaps providing localchemotherapeutic agents, decreasing production of scar tissue, and onconjunctival closure with antibiotic release. In penetratingkeratoplasty, the sutures hold the graft, as well as release antibioticand immunosuppressant agents.

EXAMPLES Example 1 Levofloxacin-Containing (L-lactic acid) (PLLA)Microfibers

Polymer and drug were dissolved in chloroform and the resulting solutionwas electrospun to form the fibers. The suture average diameter was 46±8μm and the stress 61±1 MPa.

For the in vitro drug release assay, four milligrams of fibers wereweighed, placed in tubes filled with buffered saline, and kept in anincubator shaker at 37° C. for 10 days. The in vitro release assay wascarried out in triplicate. At selected intervals, supernatant was testedwith high performance liquid chromatography (HPLC) to quantify the drugrelease. The fibers were morphologically evaluated by light and scanningelectron microscopy and the tensile strength measured. HPLC demonstrateddrug release within the first hour followed by a sustained release forat least ten days.

Antibacterial efficacy was performed against Staphylococcus epidermidis,by placing a piece of fiber on agar plate and incubating overnight at37° C. Levofloxacin, a third-generation fluoroquinolone, was releasedfrom microfibers and showed activity against S. epidermidis, one of themost common bacteria residing on the ocular surface.

The PLLA used in these experiments is a biodegradable synthetic polymerand has been shown to have no cellular toxicity. This study showed thatdrug-loaded microfibers have great potential as sutures capable of localdrug delivery in ophthalmic surgery.

Example 2 Preparation of Drug-Loaded Polymeric Sutures ContainingHydrophilic Polymer

Polymer Solution

Levofloxacin loaded PLLA-PEG sutures were prepared having differentconcentrations of PEG. An initial polymer-drug solution was prepared bydissolving PEG (Sigma-Aldrich, St. Louis, Mo.) at either 1 wt %, 2 wt %,or 4 wt %, along with 20 wt % of levofloxacin and 76 wt % ofPLLA(Mw=220,000 g/mol, PURAC Biochem, The Netherlands) in chloroform(Sigma-Aldrich, St Louis, Mo.). A control solution was prepared in thesame manner, however no levofloxacin was included. A PLLA-F 127 suturewas prepared from an initial polymer-drug solution prepared bydissolving Pluronic-F 127 (2 wt %) with 20 wt % of levofloxacin and 78wt % of PLLA in chloroform. All solutions were kept at room temperatureand stirred for approximately three days, resulting in homogeneous,viscous solutions.

Polymer Extrusion System

The experimental set up was a polymer extrusion system having a highvoltage power supply, a syringe pump, a needle syringe and a grounded 20cm diameter motor-run rotating metal disc. High voltage DC power wasapplied to the solution by clamping an electrode on the blunted needle.With 5 kV applied voltage and a 12 ml/h feed rate, applied voltageinitiates a polymer jet, which contacts a 100% ethanol (Pharmco-Aaper,Brookfield, Conn.) bath on the metal disk to extract the solvent. Theliquid reservoir was 5 cm away from the needle opening. Angular velocityof the collection wheel was adjusted by a DC motor controller (Dart15DVE) unit, usually in the range of 20˜40 rotation/min (correspondingto a distance of approximately 20-40 cm/sec). The fibers were collectedfrom the disc and dried in a vacuum chamber for two days, allowing thesolvents to evaporate. The fibers were then stored in dry conditions andkept at −20° C. for further analyses. The same procedure was repeatedwith the control solution.

Upon drying, the levofloxacin loaded PLLA-PEG fibers prepared from the 1wt % PEG solution (PLLA-PEG 1%) contained approximately 1 wt % PEG and10 wt % levofloxacin. Upon drying, the levofloxacin loaded PLLA-PEGfibers prepared from the 2 wt % PEG solution (PLLA-PEG 2%) containedapproximately 2 wt % PEG and approximately 10 wt % levofloxacin. Upondrying, the levofloxacin loaded PLLA-PEG fibers prepared from the 4 wt %PEG solution (PLLA-PEG 4%) contained approximately 4 wt % PEG andapproximately 10 wt % levofloxacin. Assuming all chloroform is remoedupon drying, the percentages of PEG in the dried suture is 1%, 2, and4%, and the percentage of levofloxacin is 10%.

Example 3 Characterization of Drug-Loaded, Polymeric Sutures

HPLC Analysis

Samples were analyzed using a Waters 1525 binary HPLC separation module,equipped with a Waters In-Line degasser AF, a Waters 717 plusautosampler (kept at 4° C.), a Waters 2998 photodiode array detector, aWater 2475 multi λ fluorescence detector, controlled by Waters Empowersoftware. Isocratic separations were run on a Waters Symmetry™ 300 C18 5μm column with 0.1% v/v TFA in H₂O:ACN (85:15 v/v) at flow rate 1mL/min. Elution was simultaneously monitored by PDA detector (collectingUV-Vis spectra from 190-800 nm every 2 seconds, which can be used toobtain chromatograms at the desired wavelength in this range and UV-Visprofile of eluting compound present within given peak) as well asfluorescence detector with 1 channel set to detect the Levofloxacin withexcitation at 290 nm and emission at 502 nm.

To obtain calibration curves and determine the limits of detection (LOD)for Levofloxacin, different amounts of drug (ranging from 1 pico gram to1 micro gram) were injected on the column and used as external standardfor quantification of the drug release from the fiber in vitro Excellentlinearity (R=0.997) in the wide concentration range for the drug wasobserved. Measured limits of detection for Levofloxacin using absorbanceat 295 nm and florescence (ex295/502 nm) were 1 ng with N/S=6.46 (noiseto signal ratio) and 1 pg with N/S=13.67 injected on the column,respectively. Triplicated injections of 100 μL for each sample wereperformed. The use of a PDA detector allowed for a confident assignmentof the peak related to Levofloxacin, not only based on its retentiontime but also based on its UV-Vis profile.

Fluorescence Spectroscopy

To obtain the optimal conditions for the Levofloxacin, fluorescencespectra of were recorded in 0.1% TFA in a solution containingwater:acetonitrile (85:15 v/v) and at concentration of 1×10⁻⁶ g/mL,using a Shimadzu RF-5301 Spectrofluorometer.

Drug Release In Vitro

One centimeter of fiber from Example 1 was placed in 1 mL of PBS buffer(Dulbecco's Phosphate Buffered Saline 1×, ATCC, Manassas, Va.) andincubated for 1 hour, 3 hours, 6 hours, 1 day, 2 days, 3 days, 4 days, 5days, 6 days, and 7 days. For each time point 6 samples were prepared.After incubation at each time point fibers were retrieved for agar platestudies and obtained solutions were analyzed by HPLC to determine theamount of drug released. As shown in FIG. 1, release of levofloxacin wasrelatively uniform over the seven-day test period. The % release oflevofloxacin reached a maximum by day 2 and remained between 5×10⁻⁷% and15×10⁻⁷ through day 7.

FIG. 2 shows the cumulative drug release for fibers prepared from 1%PEG, 2% PEG, 4% PEG, and 2% F 127. Fibers prepared from 4% PEG exhibitthe largest burst release and the highest cumulative drug release overtime. Fibers prepared from 1% PEG and 2% PEG exhibit almost identicalrelease curves. Fibers prepared from 2% Pluronic exhibited little burstrelease and release the least amount of drug over the time. This may bedue to the presence of the more hydrophobic propylene oxide segments inthe F 127.

Morphology

The fibers were morphologically evaluated by light microscope (Zeiss)and scanning electron microscope (LEO Field Emission SEM, LEO/ZeissField-emission SEM, Germany). Under SEM, the fibers appeared to have asmooth surface with porosity. The average diameters are listed in Table3. According to data from United States Pharmacopeia (USP) the fiberdiameters correspond to 7-0 to 10-0 fibers (USP designation), diametersthat are commonly used in ophthalmic surgeries. There are no suturescommercially available for ophthalmic surgeries that can locally releasedrugs to prevent or inhibit infection, rejection, or inflammation.

TABLE 3 Average diameters (μm) of levofloxacin loaded PLLA-PEG andPLLA-F127 fibers. PEG 4% PEG 2% PEG 1% F127 % AV SD AV SD AV SD AV SD61.4 ±8.4 37.5 ±7.4 82.6 ±22.2 76.6 ±5.1

Mechanical Testing

Tensile tests over single polymer string were performed with a DMA Q800unit (TA Instruments, New Castle, Del.). Samples of 5 mm of length wereall in string form and their diameters were determined with lightmicroscopy. Other parameters like length and force were measured andcontrolled by equipment. All samples were stretched until breaking.Sample modulus was calculated with the linear segment of the stretch andstrain curves. Both microfibers levofloxacin-PLLA-PEG and PLLA-PEG hadan average tensile strength of 1.8 GPa±457 MPa.

Example 4 In Vivo Studies of Drug-Loaded, Polymeric Sutures

Fifteen female Sprague-Dawley rats (Taconic Farms, Inc., Germantown,N.Y.), weighing approximately 200-300 g, were intraperitoneallyanesthetized with a Ketamine (75 mg/Kg)/Xylazine (5 mg/Kg)(Sigma-Aldrich, St. Louis, Mo.) combination. A drop of proparacainehydrochloride ophthalmic solution 0.5% (Bausch & Lomb Inc., Tampa, Fla.)was applied to the cornea. Throughout the animal study, the protocol ofthe “ARVO Statement for the Use of Animals in Ophthalmic and VisionResearch” was followed.

The 15 rats were divided into three groups consisting of a control 9-0Nylon suture, a control PLLA-PEG 2% suture, and a drug loadedlevofloxacin-PLLA-PEG 2% suture. Approximately 1 cm of suture was placedinto the corneal stroma.

The rats were evaluated for signs of infection every two days after thesurgery. Seven days after the placement of the sutures the rats wereeuthanized and the corneas extracted and fixed for 24 hours in 4%paraformaldehyde. The corneas were embedded in paraffin, crosssectioned, and stained with hematoxylin and eosin for furthermicroscopic study. The distribution of the active agent in the eye isdescribed in Table 4. The data in Table 4 is shown graphically in FIG.3.

TABLE 4 Amount of drug detected in the cornea, in the aqueous humor,remaining in the suture and the total amount of drug detected andreleased from an approximately 1 cm suture prepared from levofloxacinloaded PLLA-PEG 2% fibers and placed on the corneal stroma of femaleSprague-Dawley rats as a function of time (hours). Remained Total drugdrug Time Cornea Aqueous in suture detected released (hrs) (ng) (ng)(ng) (ng) (ng) 2 2.90 0.85 1531.76 1535.51 436.01 4 2.00 0.86 895.62898.49 1069.28 6 7.23 0.42 665.93 673.58 1294.19 8 1.51 0.18 635.34637.03 1330.74 12 1.48 0.35 894.58 896.41 1071.36 24 0.28 0.00 474.87475.15 1492.62 48 2.73 0.00 818.47 821.21 1146.56 72 1.22 0.04 1088.251089.51 878.26 96 1.15 0.02 695.97 697.14 1270.63 120 0.46 0.18 1291.131291.78 675.99 144 1.35 0.18 477.30 478.84 1488.93 168 0.51 0.04 522.85523.40 1444.37

Example 5 In Vitro Antibacterial Study of Drug-Loaded, Polymeric Sutures

Bacteria Inhibition Zone

Fiber samples were incubated in PBS buffer to measure the drug releasefor 1 to 7 days at 37° C. The fibers were retrieved and incubated at 37°C. overnight on LB agar plates (Sigma-Aldrich, St Louis, Mo.) inoculatedwith Staphylococcus epidermidis (ATCC, Manassas, Va.) to evaluate theinhibition of bacteria growth. Zones of microbial inhibition around thedrug-loaded fibers were measured at 24 hours. Negative and positivecontrols were done as well. The bacteria inhibition zone showed thatantibiotic was released from the microfiber in a necessary amount toinhibit/prevent bacteria growth around it.

The quantification of the bacterial inhibition zone is shown in FIG. 4.Drug release in vitro, measured by high performance liquidchromatography (HPLC) showed a sustained and detected drug release formore than 3 months at a level capable of inhibiting/preventing bacterialgrowth.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs. Publications cited herein andthe materials for which they are cited are specifically incorporated byreference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1-20. (canceled)
 21. A method of making a suture comprising one or morefibers, comprising extruding a jet onto a spinning device, wherein thejet comprises an electrically charged solution comprising a polymer andoptionally one or more therapeutic, diagnostic, or prophylactic agentsin a solvent, and drying the jet to form fibers.
 22. The method of claim21, wherein the spinning device contains another solvent capable ofextracting the solvent of the jet upon contact.
 23. The method of claim21, wherein the spinning device has an angular velocity in the rangebetween 20 to 40 rotations per minute or permits a travel distancebetween 20 and 40 centimeters per second.
 24. The method of claim 21,wherein the jet is dried by evaporating the solvent in a vacuum chamber.25. The method of claim 21, wherein the suture is in the form of abraided or multifiber suture.
 26. The method of claim 21, wherein thesuture has a diameter between about 10 μm and 100 μm.
 27. The method ofclaim 21, wherein the suture has a diameter between 20 tm and 60 μm. 28.The method of claim 21, wherein the suture has a tensile strength of atleast 600 MPa.
 29. The method of claim 21, wherein the suture has atensile strength between 1.3 GPa and 2.3 GPa.
 30. The method of claim21, wherein the polymer comprises a biodegradable, biocompatible polymerselected from the group consisting of polyhydroxyacids,polyhydroxyalkanoates, polycaprolactones, polyanhydrides, polyesters,hydrophobic polyethers, and copolymers thereof.
 31. The method of claim21, wherein the electrically charged solution further comprises ahydrophilic polymer selected from the group consisting of apoly(alkylene glycol), a polysaccharide, poly(vinyl alcohol),polypyrrolidone, a polyoxyethylene block copolymer, or a copolymersthereof.
 32. The method of claim 31, wherein the amount of thehydrophilic polymer is from about 1 to about 10% by weight of thefinished fibers.
 33. The method of claim 21, wherein solution comprisesone or more therapeutic agents selected from the group consisting ofanti-glaucoma agents, anti-angiogenesis agents, anti-infective agents,anti-inflammatory agents, growth factors, immunosuppressant agents,anti-allergic agents, and combinations thereof.
 34. The method of claim33, wherein the anti-infective agent is levofloxacin.
 35. The method ofclaim 21, wherein the solution comprises one or more therapeutic,diagnostic, or prophylactic agents that are released at an effectiveamount from the suture for at least seven days after placement.
 36. Themethod of claim 30, wherein the amount of the biodegradable,biocompatible polymer is from about 75 wt % to about 85% by weight ofthe finished fibers.
 37. The method of claim 21, wherein the amount ofthe therapeutic, prophylactic, or diagnostic agent is between about 0.1%and about 50% by weight of the finished fibers.